Aberrant gene expression, often involving the replacement of the adult isozymes by the embryonic form (and the reverse), occurs during the neoplastic transformation and tumor progression. The objective of the present investigation is to show in different model systems that such changes may occur in response to the selective pressure of chemotherapeutic agents, to show that differential changes in the concentration of these isozymes are related to their relative affinities for the chemotherapeutic agent, and to correlate these changes with the development of tumor cell resistance. A second, important objective is to devise means of taking chemotherapeutic advantage of these changes in order to maintain a high chemotherapeutic index. Such phenomena will occur in those instances where key enzymes (proteins), which mediate the effects of the agents, exist in multiple molecular forms which change quantitatively during development and which have different specificities. Thus the key enzyme (protein) is often not deleted in resistant cells, but is replaced with an enzyme of different specificity. Furthermore, the change in specificity under these circumstances becomes predictable and appropriate modifications can be made in the structure of the chemotherapeutic agent to cope with the changes in resistant cells. In some cases the appropriate complementary analogs are already available. The proposed study will involve the comparison of the properties (including specificities) of (1) uridine kinase isozymes and (2) the glucocorticoid-binding proteins in embryonic and adult tissues and in tumors before and during chemotherapy with (a) pyrimidine analogs and (b) cortisone, respectively. A close correlation between the change in isozyme (protein) type and the development of resistance will provide a rational basis for the substitution of the chemotherapeutic agent with a related analog to obtain continued therapeutic effectiveness.